Drop In Plasma Concentration Research Articles

Evaluation of the single dose and steady state pharmacokinetics of a progeseterone vaginal ring

OBJECTIVE: To evaluate systemic progesterone pharmacokinetics following intravaginal administration during two 7-day application cycles of a weekly progesterone vaginal ring (VR) in postmenopausal women pre-treated with estrogen. DESIGN: Open-label, one-treatment, two dose bioavailability study. MATERIALS AND METHODS: A total of 30 postmenopausal women (mean age 55.6) were pretreated with 28 days of oral estradiol prior to VR insertion and plasma pharmacokinetics of the weekly ring were evaluated during 2 consecutive 7-day dosing cycles. The second ring was removed 168 hours (Day 15) after insertion (336 hours after the first ring insertion). Blood sampling occurred from 48 hours prior to the first ring insertion (Day-2) until 48 hours after the second ring removal (384 hours after the first ring insertion or Day 17, two days after removal of the second ring). The following pharmacokinetic parameters were calculated: 1st ring insertion: Cmax, Tmax, AUC 0-168 and Cavg,ss, 2nd ring insertion: Cmax, Tmax, AUC 168-336, AUC 168-384, AUC 168-inf, Cavg,ss, Kel, and T1/2. Prior to performing any analysis, all post-dose samples were baseline-corrected. RESULTS: Steady state plasma concentrations exceeding 8 ng/mL were attained 96 hours after the first ring insertion. Except for a brief and modest fluctuation in the few hours following insertion of the second ring, plasma concentrations for the entire 7-day wear period of the second ring were essentially constant. No accumulation was observed with the use of the second ring. The AUC for the first 24-hour period was nearly identical to the AUCs for the other 6 24-hour periods in the 7-day wear period, implying a zero-order release rate. Removal of the ring resulted in a rapid drop in plasma concentration. CONCLUSION: The weekly progesterone VR provides consistent plasma levels of progesterone with minimal fluctuation between doses, rapid onset of steady state, and rapid decline after discontinuation.

Interaction Between Valproate and Meropenem: A Retrospective Study

Valproate and meropenem are frequently used in the intensive care unit to treat seizures and serious infections, respectively. Several case reports have described a remarkable interaction between the drugs when administered concurrently. The interaction leads to a significant drop in plasma concentrations of valproate within 24 hours and relapse of seizures in some patients. To evaluate a consecutive population of hospitalized patients who were simultaneously treated with meropenem and valproate and assess the effect on epileptic activity. A retrospective study of an 18 month period was performed to assess the extent and clinical impact of this interaction. To assess the relevance of the interaction, the time-relationship between the drop in plasma concentrations and relapse in seizure activity and/or deterioration of electroencephalogram recordings was determined. We investigated other contributing proconvulsive cofactors and concomitant antiepileptic treatment. Drug interaction probability scale (DIPS) scores were calculated. Thirty-nine patients were treated simultaneously with valproate and meropenem. The pharmacokinetic interaction was observed in all 39 patients, with an average drop in valproate plasma concentrations of 66%. The decrease occurred within 24 hours, as shown in 19 patients who had daily plasma concentration monitoring. The clinical impact of the interaction could not be assessed in 19 (49%) patients due to death (n = 13) or incomplete charts (n = 6). In the remaining 20 (51%) patients, DIPS scores were calculated and clinical relevance was assessed. The interaction was considered to be probable in 16 patients and possible in 4, as calculated by the DIPS. The interaction contributed to electroclinical deterioration in 11 patients. The pharmacokinetic interaction between valproate and meropenem was present in all patients and led to a drop of valproate concentrations with an average of 66% within 24 hours. This interaction was clinically relevant with electroclinical deterioration in 55% of patients. To avoid patients' possible neurologic deterioration, meropenem and valproate should not be administered together.

Marked Interindividual Variability in the Response to Selective Inhibitors of Cyclooxygenase-2

Variability in response to drugs may influence both efficacy and safety. Cyclooxygenase (COX)-2 inhibitors pose a cardiovascular risk by potentially increasing the likelihood of thrombosis, hypertension, and atherogenesis. Differences between individuals in the response to COX-2 inhibitors would be expected to influence their susceptibility to cardiovascular complications. We examined the variability in degree and selectivity of COX-2 inhibition in humans in response to celecoxib and rofecoxib. Fifty healthy volunteers received placebo, rofecoxib (25 mg), and celecoxib (200 mg), randomized by order. COX-1 and COX-2 inhibition was determined using ex vivo and in vivo indices of enzymatic activity. A subset of 5 individuals underwent 5 replicate studies to estimate variability in drug response both within and between subjects. Despite the higher COX-2 selectivity of rofecoxib in vitro, the average selectivity attained by 25 mg rofecoxib and 200 mg celecoxib in vivo were not different. However, there was considerable variability at an individual level in the degree of COX-2 inhibition and selectivity attained by both drugs. Approximately one third of the variability was attributable to differences between individuals, suggesting the contribution of genetic sources of variance, such as candidate polymorphisms detected in COX-1 and CYP2C9. The actual degree of selectivity for inhibition of COX-2 achieved by the coxibs relates both to chemical properties of the drug and to factors within an individual that modulate drug response. These sources of variability might be exploited to identify patients uniquely susceptible to benefit or at developing risk of cardiovascular complications.

Detection of Diffuse Skeletal Lesions by Monitoring the Kinetics of Labeled Phosphonate

A method of detecting of diffuse skeletal involvement in patients with metastatic tumors or with metabolic diseases is presented. The study consisted of 31 patients without bone disease and of 26 selected patients with diffuse skeletal involvement. The kinetics of 99mTc-dicarboxypropane diphosphonate (DPD) were calculated by monitoring the plasma and urine concentrations up to 5 hours after administration. Using these data, the renal clearance as well as the increase in urinary excretion of 99mTc-DPD were determined. The results indicate that measurement of the quantity of 99mTc-DPD excreted in the urine after 3 hours allows a reliable separation of the patients with diffuse skeletal lesions from normals. Other calculations such as renal clearance as well as the drop in plasma concentration were less sensitive. The test may be performed simultaneously with bone scintigraphy without additional radiation burden to the patient.

Assessment of enterohepatic circulation of radioactivity following a single dose of [14C]nimodipine in the rat.

4 male Sprague-Dawley rats with bile-duct fistulae were joined in a cascade. The first animal was given 5 mg/kg of [14C]-labelled nimodipine administered intraduodenally as a bolus. The bile of animals 1 and 2 was dynamically infused intraduodenally respectively into animals 2 and 3 and the bile of animal 3 was collected in fractions and infused i.d. into animal 4. The excretion and the course of the plasma concentration were studied radiometrically. The described investigation technique allows a detailed determination of the quantity and the kinetics of reabsorption and excretion during each observed pass of radioactivity in the enterohepatic circulation. On the basis of the balance between radioactivity administered and recovered and of the course of the plasma concentration it has been shown, on the example of nimodipine, that the experiment successfully simulates the situation in the intact animal. The [14C]Nimodipine radioactivity is subject to pronounced enterohepatic circulation: on average 43% of the amount excreted with the bile is reabsorbed with each recirculation and 57% is excreted with the faeces, 81% and 19% of the quantity reabsorbed being excreted respectively with the bile and urine. Because of the repeated reabsorption, the effective dose is increased by 54% and the drop in plasma concentration is slowed down in the middle time interval between 3 and 15 h after administration. The kinetic processes (absorption, excretion) become slower with each recirculation. An increasing fraction of the absorbed radioactivity undergoes direct hepatic excretion, by-passing the systemic circulation.

Pregnancy and fetal development in epileptic women

Epilepsy affects almost 1% of all pregnant women. Epileptic women marry more often than epileptic men. Married epileptic women have a lower socio-economic status and are more severely ill than married male epileptics.--Several reasons are discussed--poor compliance being probably the most essential one--for an explanation of an occasional increase in the rate of attacks and a frequently observed tendency to a drop in plasma concentrations of anti-epileptics during pregnancy. Pregnancy and parturition are not more complicated in epileptic women than in non-epileptics women. Nevertheless, abortions are performed, and delivery by surgery is initiated, more often with epileptics, although there are no convincing arguments in favour of such procedures. For unknown reasons, perinatal lethality is up to twice as high than with controls.--Children of mothers treated with anti-epileptics have a tendency to intrauterine dystrophia, which is manifested mainly by a reduced size of the head which is not made up completely during the first few years of life, contrary to other body dimensions. We do not know as yet whether there are any links between dystrophia of the body, malformations and inhibited psychomotoric development.--Depending on the type of anti-epileptics given to the mothers who are breast-feeding their children, and on the concentration of these drugs in the plasma or in the mother's milk, breast-fed children may display signs of withdrawal or sedation. This must not be overlooked when considering the problem of breast-feeding.--The slightly enhanced risk of malformations appears to be less intimately connected, with intrauterine exposition of anti-epileptics than with the underlying disease itself.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolism and distribution of primaquine in monkeys.

Rhesus monkeys were administered primaquine diphosphate (6.0 to 10.5 mg/kg, I.V.), and plasma samples were analyzed by high performance liquid chromatography for the presence of the unchanged drug and the major metabolite , 8-(3-carboxy-l-methylpropylamino)-6-methoxyquinoline (II). Primaquine had an unusually high affinity for tissue compartments which produced a rapid initial drop in plasma concentration. Within 15 minutes, the plasma concentration of II far exceeded that of primaquine. 35 to 83 % of the primaquine dose was converted to II; moreover, metabolite II possessed much lower affinity for the tissue compartments than primaquine itself.

Comparison of the Effects of Whole-Body X-Irradiation and Fasting on the Plasma Lipids of Mice

Blood lipid changes in mice subjected to whole-body irradiation were investigated. Fatty acid distributions were determined by gas chromatographic techniques. The low-density lipoproteins (LDL) showed a signfficant drop in plasma concentration after irradiation. Alterations in fatty acid distribution in total plasma may be due to the LDL decreases associated with irradiation. Similar investigations were carried out on mice subjected to a 24hour fasting period. Whereas the LDL and plasma glycerides displayed significant reductions, the high-density lipoproteins (HDL) and phospholipids increased in plasma concentrations. In addition the fatty acid distributions of the LDL, HDL, and plasma glycerides of the fasted mouse showed some significant differences when compared with the controls. (auth)